This research program seeks to define the molecular basis of Rh antigenicity in the human erythrocyte plasma membrane. Most of the studies have involved work with a membrane fraction obtained by alkaline extraction where about half the proteins are removed and where the only proteins left are those commonly denoted as integral. Investigations with both immune anti-Rh and non-immune immunoglobulin G (IgG), utilizing both Rh-positive and Rh-negative membrane fractions, have shown that three polypeptides are involved in IgG binding in the immune system while only two are seen in the non-immune and Rh-negative controls. The polypeptide unique to the Rh0(D) antigen has an apparent molecular weight of about 90,000 and thus may be a subcomponent of the largest polypeptide po;ulation in the red cell membrane, often called band 3. Certain aspects of integral membrane protein behavior, discerned in our studies will likely be relevant to many biomembrane studies. These would include the critical importance of sulfhydryl behavior, non-enzyme mediated autolysis and susceptibility to oxidative damage.